Abstract
Biological ion channels are integral membrane proteins that are usually formed by relatively large proteins. Studying current-voltage (I-V) characteristics of channels is commonly used to understand how channels function and estimate effectiveness of existing and potential drugs. The current - voltage characteristics of a channel depend on the channel's structure and conformation. Current conduction through a channel in the protein is a slow process, which makes the traditional methods for theoretical modeling of proteins (such as molecular dynamics or Monte-Carlo simulations) practically inapplicable for direct modeling of channel function. Therefore other simplified theoretical methods have been developed. One such method is the Poisson-Nernst-Plank (PNP) theory of electro-diffusion, where a set of partial differential equations (the Poisson and the Nernst-Plank equations) are solved self-consistently. We are developing the PNP equations solver (PNPS) for calculating current-voltage properties of ion channel proteins. To improve computational efficiency the solver was parallelized. The new solver has been applied to predict ion conductance properties of the α-Hemolysin channel, a robust and well studied pore forming heptameric protein complex. Because of the asymmetry of the protein structure its position with respect to the lipid bilayer has not been well determined. We performed a series of calculations in which the membrane position has been varied. pKa calculations show that the protonation state of some residues depends on the membrane position. The results of PNP calculation are compared with experimental data on channel conductance, ion selectivity, reverse potential, rectification properties. Such detailed analysis allowed us to pinpoint position of the protein in the membrane. Several methods for setting diffusion coefficients were tested. We have also investigated models for interaction of a permeant ion with the protein and its mobility in the constricted environment of the protein pore.
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